Delivery of genes capable of interfering with the intracellular replication cycle of HIV provides a novel therapeutic approach to treat or prevent HIV infection by gene therapy has been limited by difficulties in efficiently delivering the therapeutic gene into cells that are the primary targets of HIV infection. This limitation is being addressed by Dr. Strayer (Project #1) by the development of new SV40-based vectors capable of targeting hematopoietic stem/precursor cells, monocyte/macrophages and T cells. To evaluate the clinical usefulness of these new vector systems, it will be necessary to determine their capacity to transduce human hematopoietic precursor stem cells, by expressed in their mature progeny cells and protect the cells from in vivo HIV infection. By transplanting SCID mice with human fetal bone marrow and/or implanting them with human fetal thymus, we have developed an animal model that displays long-term human hematopoiesis in the mouse bone marrow and human thymopoiesis in the thymic implant that is associated with population of the murine periphery with human myeloid and T cells. We have demonstrated that these are a useful system for the in vivo assessment of hematopoietic stem/precursor cell-targeted gene therapy. The development of systemic HIV infection after intraimplant or i.p. inoculation by these mice makes them an attractive system for evaluating the effect of gene therapy on in vivo HIV infection. Therefore, we propose to use these systems to examine their in vivo capacity to transduce hematopoietic stem/precursor cells and thereby be expressed in the progeny cells or to directly target and mediate expression of the inserted gene in human T cells and monocytes. We will evaluates the function of the vectors by challenging the mice with HIV and thereby determining the capacity of these vectors to protect human cells from in vivo HIV infection. In addition, we will also evaluate the effect that transduction with these different vectors has on the subsequent hematopoiesis and thymopoiesis that occurs in these mice.